Effects of an α2-adrenoceptor antagonist on glucose tolerance in the genetically obese mouse ( [formula omitted][formula omitted

Abstract

This study examines the effects of a relatively selective α 2-adrenoceptor antagonist, 8-( l-piperazinyl)imado-[1,2-α] pyrazine (compound A), and the preferential α 2-agonist clonidine on blood glucose, glucose tolerance, and plasma insulin levels in the C57BL 6J ob ob mouse and its lean littermate. While clonidine raised blood glucose levels and impaired glucose tolerance, oral administration of compound A resulted in decreased blood glucose levels, as well as improved glucose tolerance in ob ob mice. Insulin levels in ob ob mice treated with clonidine were significantly reduced, while compound A raised insulin levels threefold and blocked the effects of clonidine when co-administered to the same animals. Clonidine-induced hyperglycemia in lean littermates was not accompanied by a decrease in insulin levels, while a small but significant increase in insulin levels was observed by compound A administration. Glycogen synthesis in diaphragm of ob ob mice was enhanced after oral administration of compound A and was accompanied by an increase in plasma insulin levels. Concomitant treatment with a potent somatostatin analog to inhibit insulin release blocked the effects of the α 2-adrenoceptor antagonist, compound A. These observations suggest that the α 2-antagonist studied, increased plasma insulin levels with an accompanying reduction in blood glucose and an improvement in glucose tolerance in a genetic model of insulin resistance. Differential sensitivity to α 2-agonist in these genetically obese mice, ob ob , was demonstrated by decreased insulin levels due to clonidine administration.